Fig. 2

Rejuvenation of transgenic progeric mice by cyclic partial cell reprogramming. A polycistronic cassette (4F system) harboring the four Yamanaka genes under the control of a tetracycline-regulatable (Tet On) promoter (a) was transferred to one-cell embryos of C57bl/6 wild-type mice in order to generate transgenic mice harboring the 4F system (4F mice) that were subsequently backcrossed with transgenic progeric mice (LAKI mice). This way, progeric LAKI-4F mice were generated. The antibiotic doxycycline (DOX) binds to the regulatory rtTA protein which then gains affinity for the Tet On promoter and binds to it turning on the Yamanaka genes (b). When DOX is removed from the medium, the rtTA protein dissociates from the promoter and the transgenes become silent again (c). When DOX was added to the drinking water of 2-month-old progeric mice, it turned on the Yamanaka genes and partial cell reprogramming began (d). Two days later, DOX was removed and the Yamanaka genes silenced (e). After a 5-day resting period, DOX was added again for 2 days (f), then removed for 5 days and so on. This cyclic partial reprogramming process rejuvenated some tissues and organs of the mice which survived 50% longer than the original progeric mice, see [16] for further details